Propane-1-sulfonicacid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide or Vemurafenibis a low molecular weight, orally available, inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAF.
Vemurafenib was approved by USFDA in 2011 and is marketed under the brand name Zelboraf®, has been shown to cause programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway—if the B-Raf has the common V600E mutation.
Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by Vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases
Vemurafenib is chemically known as propane-1-sulfonic acid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(I). Vemurafenib is a white to off-white crystalline solid with the empirical formula C23H18ClF2N3O3S and a molecular weight of 489.99. It is practically insoluble in aqueous media.
As per the Chemistry review available in Drugs@FDA for Vemurafenib. Drugs substance contain “Five impurities are specified at levels exceeding this applicable qualification threshold because they have been detected in DS batches in amounts that exceeded the qualification threshold Data from appropriate toxicology studies are provided to qualify the proposed limits. Thirty four development or pilot scale batches and eight commercial scale batches have been reported. Specifications and analytical methods have been established to adequately control the identity, quality, purity and stability of the drug substance.”
Further, as per the Pharmacology review available in Drugs@FDA for Vemurafenib “A single impurity was identified during the course of the review as being above the level for qualification. The specification for this impurity is . . . % and it was qualified in the 13-week dog study. Other impurities discussed with the chemistry review team did not exceed the 0.15% level described in the ICH Q3A(R2) guidance and, therefore, did not require qualification in animal studies.”
As per the scientific discussion “Vemurafenib can exist as several polymorphs and solvates. The crystalline Form II is thermodynamically the most stable. Crystalline Vemurafenib (Form II) is a white to almost white non-hygroscopic powder with a melting point of about 271° C. Its solubility in water is very low (<0.0001 mg/ml) and it is not appreciably soluble in many common organic solvents either. When processed with HPMC-AS, Vemurafenib becomes an amorphous white to almost white powder which is slightly hygroscopic. The product with (HPMC-AS) is non-crystalline.”
From the above citations it is abundantly clear that Vemurafenib marketed in the form of crystalline Form II, contains inherently a known impurity, which is exceeding the requirement of ICH guidelines, which was subsequently attempted to get qualified in the 13-week dog study. In view of the aforementioned disclosures, there appears to be a need for development of substantially pure Vemurafenib, which meets the requirements of ICH guidelines from impurities perspective besides maintaining the stability for longer durations.
Vemurafenib is generically disclosed in U.S. Pat. No. 7,504,509, however, there is no specific disclosure of the structure in this patent. Vemurafenib is specifically disclosed in U.S. Pat. No. 7,863,288 and more specifically U.S. Pat. No. 8,143,271.
Disclosures of US patent '288 and US '271 both disclose same process for the preparation of Vemurafenib. The process disclosed specifically for the preparation of Vemurafenib is delineated below:

These patents do not provide and insight about the impurity concern as well as disclosure of any purity of the final product. However, it is clear from Drugs@FDA that the product obtained as per the process is exceeding in the levels of impurity than the applicable qualification i.e., exceeding 0.15% level as described in the ICH Q3A. In view of this it is necessary to develop a process resulting in the product, which is complying with the ICH requirements of quality parameters.
U.S. Pat. No. 8,741,920 and its corresponding equivalents U.S. Pat. No. 8,329,724 and U.S. Pat. No. 8,530,661 discloses a different process for the preparation of Vemurafenib. The process is as disclosed below:

These patents further disclosed two compounds A and B, which are by-products for the route of synthesis disclosed in these patents

These patents have not disclosed any generalized impurities formed during the process development. Further, these patents have also not disclosed perfect (real) purity obtained as per this process, these patents broadly mentioned the purity as ≥99% and does not disclosed the content of total impurities formed in the final active pharmaceutical ingredient (API).
Further, it mentions that “the impurity/trace amounts of the compound of formula (B) will not affect the pharmacological or toxicity profile of any potential future medicament or pharmaceutical preparation containing Vemurafenib, said compound may serve only as a way of detecting the apparent process has been used to manufacture the Vemurafenib”
A reproduction of an earlier patent process U.S. Pat. No. 7,863,288 though indicates the presence of said compound, however materially questions as to how it serves any purpose/merit in US '920.
Inventors of the present application during extensive evaluation observed that such compound of Formula (B) may be more often formed from the key starting material (4-chlorophenyl boronic acid), which is also known to be used earlier process disclosed in US '288. In the process of purification according to the present invention, it results in providing a highly pure/substantially pure Vemurafenib, which may also be devoid of such compound of formula (B) with exceeding purity of >99.5% (By HPLC).
Inventors also observed that such compound of formula (B) formation may also be avoided if the key starting material (4-chlorophenyl boronic acid) is purified prior to any condensation reaction under modest conditions. This also serves as an embodiment according to the present invention.
Prabha. N. Ibrahim et al. in U.S. Pat. No. 8,865,735 disclosed a solid form of Vemurafenib, wherein said solid form is selected from the group consisting of                a) a substantially amorphous form of compound 1 selected from form XXIV, XXV, XXVI or combinations thereof, wherein the compound 1 is molecularly dispersed;        b) a solvate selected from form III, IV, V, VI, VII, IX, X, XI, XII, XIII, XIV or XV;        c) a polymorph selected from form VIII or XVI; and        d) the sulfuric acid-, hydrobromic acid- or hydrochloric acid salt of Vemurafenib.Further, this patent discloses that the amorphous form of Vemurafenib is preferentially substantially pure, meaning the amorphous form includes less than 0.1% by weight of impurities, including other polymorph forms of Vemurafenib. At least about 30-99.9% by weight of the total of Vemurafenib in the composition is present as the amorphous form. This patent not disclosed any generalized impurities formed during the process development and not disclosed the purity obtained as per this process. This patent mentioned the amorphous Vemurafenib obtained as per the process has a polymorphic purity of at least about 99.9% by weight.        
Prabha. N. Ibrahim et al. in US 2014/0094611 disclosed a process for the preparation of Vemurafenib. The process disclosed is as summarized below:

Dipen Desai et al. in US2010/0310659 disclosed different crystalline forms like crystalline Form-1, crystalline Form-2, mesylate salt, tosylate salt, maleate salt, oxalate salt and dichloro acetate salt of Vemurafenib. This patent publication has also not disclosed the purity of the products obtained as per this patent publication. Further, as it is quite clear from EMEA and Drugs @FDA that the marketed form is Form-II that contains a known impurity, which is exceeding the requirement of ICH guidelines. This patent publication further discloses pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylene diamine, meglumine, hydroxyl ethylpyrrolidine, piperidine, morpholine, piperazine, procaine, aluminum, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium, and mono-, di-, or tri-alkylamines (e.g. diethylamine), or salts derived from amino acids such as L-histidine, L-glycine, L-lysine, and L-arginine.
Frank Lehmann et al. in WO 2014/008270 discloses Choline salt and esylate salt of Vemurafenib. This patent also disclosed N-methyl Vemurafenib and crystalline T-1 form of Vemurafenib. The maximum purity disclosed for Choline salt is 99.4%. WO '270 not disclosed any purity of esylate salt of Vemurafenib. WO '270 also disclosed the purity of N-methyl Vemurafenib as 96.89%.
Wolfgang Albrecht in WO 2014/159353 discloses Hydrochloride salt of Vemurafenib. This patent publication not disclosed any purity for Vemurafenib hydrochloride obtained as per the patented process. The process disclosed in this patent publication involves stirring over night to form the hydrochloride salt, which is cumbersome and longtime stirring may leads to the formation of process related impurities. Further, the present inventors repeated the process and the purity obtained by HPLC analyzed and found to be 98.13.
In view of the above it is pertinent to note that there is a need to develop new salt forms of Vemurafenib as well as free base of Vemurafenib having further improved physical and/or chemical properties besides high purity levels. Hence it was thought worthwhile by the inventors of the present application to explore novel pharmaceutically acceptable salts of Vemurafenib, which may further improve the characteristics of drug Vemurafenib and in developing the substantially pure Vemurafenib. Low aqueous solubility is the major problem encountered with formulation development.
As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/bioavailability and other pharmaceutical profiles, stable polymorphic form of a drug has often remained the clear choice in compositions due to various reasons of handling, mixing and further processing including bioavailability and stability.
Exploring new process for developing a stable and pure form of Vemurafenib salts, which are amenable to scale up for pharmaceutically active/useful compounds such as Vemurafenib triflate in the preparation of Vemurafenib free base may thus provide an opportunity to improve the drug performance characteristics of products such as purity and solubility. Hence, inventors of the present application report a process for the preparation of a stable and substantially pure form of propane-1-sulfonic acid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide or Vemurafenib, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.
The present invention provides an improved process for the preparation of substantially pure propane-1-sulfonic acid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide or Vemurafenib, wherein substantially pure material having a purity of greater than 99.5% by HPLC, which is not reported earlier in the prior art and meeting the quality of ICH guidelines. Vemurafenib obtained by the process of the present invention is non-hygroscopic and chemically stable and has good dissolution properties.
In view of the above and to overcome the prior-art problems the present inventors had now developed an improved process for the preparation of substantially pure Vemurafenib, using industrially feasible and viable process, with the use of industrially friendly solvents, which does not include tedious work up and time lagging steps.